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    Summary
    EudraCT Number:2018-003682-34
    Sponsor's Protocol Code Number:CSL300_3001/VKTX01
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-03-25
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2018-003682-34
    A.3Full title of the trial
    A Pivotal Phase 3 Trial to Evaluate the Safety and Efficacy of Clazakizumab for the Treatment of Chronic Active Antibody-Mediated Rejection in Kidney Transplant Recipients
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clazakizumab for the Treatment of Chronic Active Antibody-Mediated Rejection in Kidney Transplant Recipients
    A.3.2Name or abbreviated title of the trial where available
    IMAGINE
    A.4.1Sponsor's protocol code numberCSL300_3001/VKTX01
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03744910
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCSL Behring LLC
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCSL Behring LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCSL Behring LLC
    B.5.2Functional name of contact pointTrial Registration Coordinator
    B.5.3 Address:
    B.5.3.1Street Address1020 First Avenue
    B.5.3.2Town/ cityKing of Prussia
    B.5.3.3Post codePA 19406
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1610 878 4000
    B.5.6E-mailclinicaltrials@cslbehring.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCSL300
    D.3.2Product code Clazakizumab
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCLAZAKIZUMAB
    D.3.9.1CAS number 1236278-28-6
    D.3.9.3Other descriptive nameCLAZAKIZUMAB
    D.3.9.4EV Substance CodeSUB117542
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic Active Antibody-Mediated Rejection (CABMR) in Kidney Transplant Recipients
    E.1.1.1Medical condition in easily understood language
    Kidney rejection after transplant cause by specific antibodies.
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To evaluate the efficacy of clazakizumab in preventing all-cause composite allograft loss (including death) due to CABMR.
    2. To evaluate the efficacy of clazakizumab in slowing/preventing the progressive loss of kidney function (as measured by eGFR using the Modification of Diet in Renal Disease 4 (MDRD4) equation).
    3. To evaluate the safety of clazakizumab.
    E.2.2Secondary objectives of the trial
    1. To evaluate the effects of clazakizumab on loss of allograft function (defined as a 40% decline in eGFR from Baseline that is sustained for at least 60 days).
    2. To evaluate the effects of clazakizumab on death-censored allograft loss.
    3. To evaluate the effects of clazakizumab on albuminuria.
    4. To evaluate the effects of clazakizumab on DSA titers and mean fluorescence intensity (MFI) scores.
    5. To evaluate the effects of clazakizumab on incidence of acute rejection episodes (TCMR and ABMR).
    6. To evaluate the effects of clazakizumab on the histology of kidney biopsies according to the Banff 2015 lesion grading scores.
    7. To evaluate the effects of clazakizumab on overall patient survival.
    8. To evaluate the PK of clazakizumab following subcutaneous injection in kidney transplant recipients with CABMR (for those in the PK/PD substudy only).
    9. To evaluate the immunogenicity of clazakizumab in kidney transplant recipients with CABMR
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    PK
    E.3Principal inclusion criteria
    1. Age 18 to 75 years.
    2. Living donor / deceased donor kidney transplant recipients ≥ 6 months from time of transplant.
    3. Diagnosis of CABMR determined by kidney biopsy and the presence of HLA DSA using single-antigen bead-based assays.
    NOTE: If conducted within 12 months (+ 3 weeks) prior to the start of the Screening Period and no intervening treatments have been administered, the biopsy does not need to be repeated at Screening. If conducted within 6 months (+ 3 weeks) prior to the start of Screening, the DSA analysis does not need to be repeated at Screening. To be considered for determination of study eligibility, the biopsy and DSA analysis must be performed at least 2 months ± 2 weeks after the end of any prior treatment for ABMR (including CABMR) or TCMR, in order to show continuing CABMR and presence of HLA DSA. In addition, with the exception of steroids, treatments for ABMR or TCMR are not allowed within 3 months prior to the start of Screening (see Exclusion Criterion 3).
    The following histopathologic and serologic diagnostic criteria (based on Banff 2015 criteria [Loupy et al, 2017]) must be met for inclusion:
    . Morphologic evidence of chronic tissue injury, as demonstrated by TG (cg>0). Biopsies without evidence of chronic tissue injury on light microscopy, but with glomerular basement membrane double contours on electron microscopy (cg1a) are eligible.
    . Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following.
    i. Linear C4d staining in peritubular capillaries or medullary vasa recta (Banff scores C4d2 or C4d3 by immunofluorescence on frozen sections, or C4d > 0 by immunohistochemistry on paraffin sections).
    ii. At least moderate microvascular inflammation ([g + glomerulitis score, [g] + peritubular capillaritis score [ptc] ≥ 2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥ 1.
    NOTE: The local pathologist’s diagnosis must be reviewed by a central pathologist to confirm eligibility for entry into the study. Biopsies with other histopathologic changes (eg, BKV nephropathy or recurrent glomerulonephritis) may be eligible if concurrent CABMR changes (as detailed above) are present and determined to be the predominant cause of renal dysfunction.
    . Serologic evidence of circulating DSA to HLA.
    NOTE: The local laboratory DSA results must be reviewed and confirmed by the central HLA reviewer during the Screening Period.
    4. Written informed consent obtained from subject (or legally acceptable representative) before any trial-related procedures.
    E.4Principal exclusion criteria
    1. Multi-organ transplant recipient (except for simultaneous kidney-pancreas or previous multiple kidney transplants) or cell transplant (islet, bone marrow, stem cell) recipient.
    2. Treatment for ABMR (including CABMR) or TCMR within 3 months prior to the start of Screening with the exception of steroids.
    3. Received T cell depleting agents (e.g., alemtuzumab, anti-thymocite globulin) within 3 months of the start of screening.
    4. Pregnant, breastfeeding, or unwillingness to practice adequate contraception.
    5. Active tuberculosis (TB) or history of active tuberculosis (TB).
    6. History of human immunodeficiency virus (HIV) infection or positive for HIV.
    7. Seropositive for hepatitis B surface antigen (HBsAg).
    8. Hepatitis C virus (HCV) RNA positive.
    E.5 End points
    E.5.1Primary end point(s)
    Time to all-cause composite allograft loss
    defined as
    o eGFR < 15 mL/min/1.73 m2*,
    o return to dialysis*,
    o allograft nephrectomy,
    o retransplantation, or
    o death from any cause (Final Analysis),
    *total cumulative duration of eGFR < 15 mL/min/1.73 m2 AND / OR dialysis ≥ 60 days.
    An eGFR <15 mL/min/1.73 m2 must be confirmed by a repeat measurement
    The time window for confirmation of an eGFR < 15 mL/min/1.73 m2 is ≥ 60 days from when initially noted. The date of the initial eGFR < 15 mL/min/1.73 m2 is the date when first determined from local or central laboratories.
    The primary efficacy endpoint will be analyzed as part of the final analysis when at least 221 all-cause composite allograft loss events have occurred.
    E.5.1.1Timepoint(s) of evaluation of this end point
    up to approximately 7 years
    E.5.2Secondary end point(s)
    1) Incidence and time to loss of allograft function as defined by a 40% decline in eGFR from Baseline.
    2) Incidence of time to all-cause composite allograft loss
    3) Incidence and time to death-censored allograft loss.
    4) Change in mean estimated glomerular filtration rate (eGFR) from Baseline to End of Treatment (EOT).
    5) Change in spot urine albumin creatinine ratio (UACR) from Baseline to EOT.
    6) Change in (Donor-specific antibodies) DSA titers and Mean fluorescence Intensity (MFI) scores from Baseline to EOT.
    7) Incidence of acute rejection episodes of T cell-mediated rejection (TCMR) and Antibody-mediated rejection (ABMR) from Baseline to EOT.
    8) Change in Banff lesion grading score (2015 criteria [Loupy et al, 2017]) of pre-treatment to post treatment (Week 52) kidney biopsies.
    9) Overall patient survival.
    10) Maximum concentration (Cmax, Cmax ss) of CSL300)
    11) Trough concentrations (Ctrough, Ctrough ss) of CSL300
    12) Area under the concentration-time curve (AUCO-tau ss) at steady state of CSL300
    13) Time of maximum concentration (Tmax, Tmax ss) of CSl300
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Baseline and up to approximately 7 years
    2-7) Up to approximately 7 years
    8) Up to 52 weeks
    9) Up to approximately 7 years
    10-13) Up to 21 days
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA45
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Brazil
    Canada
    Colombia
    Korea, Republic of
    Mexico
    New Zealand
    Taiwan
    United States
    Austria
    France
    Sweden
    Netherlands
    Spain
    Switzerland
    Czechia
    Germany
    Belgium
    Hungary
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years10
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years10
    E.8.9.2In all countries concerned by the trial months4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 310
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 350
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The post-trial treatment will be performed by the trial investigator and/or the patient’s non-trial physician based on guidance from the trial investigator as applicable. This could also involve further treatment with Interleukin-6 inhibitors, if required.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-05-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-17
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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